Enantioselective Synthesis of Ozanimod, the Active Pharmaceutical Ingredient of a New Drug for Multiple Sclerosis

Abstract

This paper is dedicated to Professor Franco Cozzi on his 70th Birthday. We report here a short enantioselective synthesis of Ozanimod, a potent modulator of the enzyme Sphingosine-1-phosphate receptor (S1P R), recently approved by FDA and EMA for the treatment of relapsing-remitting multiple sclerosis. Amongst different synthetic approaches explored, we achieved the best result introducing the stereogenic centre in the last step through imine asymmetric transfer hydrogenation (ATH) using Wills' catalysts. Besides the reduced numbers of enantiomeric purity controls required, this process culminates in an exceptionally high enantioselective reductive amination obtained with commercially available tethered Ru catalysts. Starting from commercially available 4-cyano-indanone, enantiomerically pure Ozanimod was obtained in 5 steps in 62 % overall yield and 99 % ee.

Overcoming a Solid Solution System on Chiral Resolution: Combining Thermodynamics of Crystallization and Kinetics of Enantioselective Dissolution

“…Although the access to the enantiopure S-1 is achieved by asymmetric synthesis using chiral Ellman's auxiliary [25] and enzymatic methods [26] , the chiral resolution of racemic form and crystal structure has not been reported so far, although salt formation with tartaric acid has been reported. [27] In this approach, after purification to moderate optical purity by thermodynamic equilibrium in a complete solid solution of the diastereomeric pair, the kinetically metastable diastereomeric pair is dissolved by immersing in the solvent for a short time. This combination overcomes the optical purity of solid solution achieved by thermodynamic equilibrium (Figure 1b).…”

Overcoming a solid solution system on chiral resolution: combining crystallization and enantioselective dissolution

“…Access to the enantiopure S-1 has been achieved by asymmetric synthesis using chiral Ellman's auxiliary [6] and enzymatic methods [7] . However, while salt formation with tartaric acid has been described, [8] the chiral resolution of the racemic form and its crystal structure have not yet been reported. In this approach, after purification to moderate optical purity by thermodynamic equilibrium in a complete solid solution of the diastereomeric pair, the kinetically metastable diastereomeric pair is dissolved by immersing in the solvent for a short time.…”